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Department of Pediatrics, Rambam Medical Center, Haifa 31096; and Dana Children’s Hospital, Tel-Aviv 64239, Israel
Address all correspondence and requests for reprints to: Dr. Z. Hochberg, Pediatric Endocrinology, Rambam Medical Center, POB 9602, Haifa 31096, Israel. E mail: z_hochberg{at}rambam.health.gov.il
Abstract
During GnRH agonist therapy of patients with central precocious puberty (CPP), growth is sometimes suppressed to subnormal velocity. The working hypotheses were that estrogen levels are suppressed by GnRH agonist therapy below normal prepubertal levels, that such suppression is responsible for the slow growth of girls with CPP during GnRH agonist therapy, and that a mini-dose of estrogen replacement will normalize growth. The present pilot study examined growth and bone maturation over 2 yr in 13 patients with CPP and compared therapy with a combination of GnRH agonist and 8 µg conjugated equine estrogen (group 1) to therapy with GnRH agonist alone (group 2). Both groups had adequate suppression of gonadotropins, and E2 levels were below detection levels of our assay throughout the study period. Group 2 patients decreased their growth velocity from 2.0 ± 1.4 to -1.6 ± 1.2 SD score compared with group 1, who maintained their growth velocity of 1.3 ± 1.5 SD score and their height SD score for 2 yr (P < 0.01). In group 1 patients the ratio of the change in bone age/change in chronological age decreased from 1.2 ± 0.7 to 0.75 ± 0.3, and in group 2 patients it decreased to 0.6 ± 0.3 and 0.4 ± 0.2 (P < 0.05) during the first and second years of therapy, respectively. It is concluded on a pilot basis that estrogen suppression is responsible for the slow growth of girls with CPP during GnRH agonist therapy and that a mini-dose of estrogen replacement is safe and effective for at least 24 months in maintaining normal prepubertal growth without acceleration of bone maturation or pubertal development. The current pilot results do not suggest an indication or provide a justification for such therapy.
RAPIDLY PROGRESSING central precocious puberty (CPP) is now universally treated with a depot preparation of GnRH agonist. The aims of such therapy are to arrest pubertal maturation and prevent early menarche as well as to slow bone maturation and improve adult height. The long-term outcome of depot GnRH agonist treatment in girls with rapidly progressing CPP improves final height significantly and nearly preserves genetic height potential when initiated before age 6 yr (1, 2, 3, 4). However, during GnRH agonist therapy of patients with CPP, growth is often suppressed to subnormal velocity (5, 6). The mechanism of that deceleration is unknown and apparently only partly dependent on the GH-IGF-I axis (7). Can the mechanism be related to suppression of E2 levels by the GnRH agonist?
Due to the depot nature of the preparations, GnRH agonist therapy is often given at a maximal dose regardless of the child’s size (3). In a dose-response study of GnRH agonist, deslorelin was shown to have a dose-dependent suppressive effect on serum estrogen, with the highest dose suppressing E2 to 6.5 ± 0.7 pmol/liter compared with reported prepubertal levels of 0.07–6.3 pmol/liter (8). Estrogen has a biphasic effect on epiphyseal growth, with maximal stimulation at low levels (9). It was shown that the administration of low dose estrogen caused more than a 60% increase over the prepubertal growth rate in both boys and girls and that a low dose estrogen treatment stimulates short-term ulnar growth in boys (10). The administration of an aromatase inhibitor to boys with familial male-limited precocious puberty reduced to near normal both growth velocity and bone maturation despite levels of serum T that remained within the adult male range (11). The presence of low levels of estrogen in prepubertal girls compared with boys (12) might also explain the more rapid epiphyseal maturation in girls.
The working hypotheses of this pilot study were that estrogen levels are suppressed by GnRH agonist therapy below normal prepubertal levels, that such suppression is responsible for the slow growth of girls with CPP during GnRH agonist therapy, and that a mini-dose of estrogen replacement to normalize prepubertal estrogen levels will normalize growth and is safe. Toward those goals, the present pilot study examined growth and bone maturation in girls with CPP and compared therapy with GnRH agonist alone to therapy with a combination of GnRH agonist and a mini-dose of estrogen.
Materials and Methods
Thirteen girls with CPP, aged 3–9 yr (median, 7.1 yr), were the subjects of the present study (Table 1
). All subjects had CPP, as determined by rapid development of breast and pubic hair before age 7 yr, acceleration of growth and bone maturation, and increased gonadotropin levels (basal FSH and LH levels >1.5 IU/liter). Magnetic resonance imaging detected no anatomical lesions in any of the patients. Three of the patients had been receiving GnRH analog therapy for 12–18 months before the study, and 10 were naive to GnRH analog therapy. GnRH analog therapy consisted of Decapeptyl (Ferring Pharmaceuticals Ltd., Kiel, Germany) at a fixed dose of 3.75 mg given im every 28 d. The efficacy of GnRH therapy was determined by monitoring suppressed LH and FSH levels.
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Mini-dose estrogen treatment was given in the form of encapsulated powder of 8 µg conjugated equine estrogen (Premaril, Dexxon). This dose was based on reported serum estrogen levels for prepubertal girls of less than 0.07–6.3 pmol/liter (12). If treatment with 625 µg conjugated estrogen produces an adult follicular level of 400 pmol/liter, the mean prepubertal level of 5 pmol/liter reported by Klein et al. (12) would be achieved with a dose of 8 µg. Compliance was monitored by a count of returned unused capsules.
Serum gonadotropins was measured by RIA (Roche Elecsys, Basel, Switzerland) with an analytical sensitivity of 0.1 IU/liter for FSH and LH. Serum E2 was measured by an Immulite assay (Diagnostic Products, Los Angeles, CA) with an analytical sensitivity of 14 pmol/liter.
SD scores were calculated according to chronological age, using GrowthVision software (Novo-Nordisk, Copenhagen, Denmark). Statistical significance comparing the two groups used the Mann-Whitney test for nonparametric data. Significance was defined as P < 0.05.
Results
Both groups had adequate suppression of gonadotropins (FSH, <0.1; LH, <0.1 IU/liter), and E2 levels were below detection levels of our assay throughout the study period (Fig. 1). E2 levels also remained below the detection level of our assay in patients in group 1 during mini-dose estrogen therapy.
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Group 2 patients decreased their growth velocity from 2.0 ± 1.4 to -1.6 ± 1.2 SD score compared with group 1, who maintained their growth velocity of 1.3 ± 1.5 SD score and their height SD score for 2 yr (P < 0.01; Fig. 2). As a result, the height of group 2 patients decreased from 1.3 ± 1.4 SD score before therapy to 0.9 ± 0.9, 0.7 ± 0.7, and 0.8 ± 0.8 SD score at 12, 18, and 24 months, respectively, whereas that of group 1 remained unchanged at 1.4–1.6 SD score (P < 0.05; Fig. 2). The pretreatment growth velocity of many of the subjects in this study was fairly low for CPP, as most were diagnosed and treated early in the course of their precocious puberty. The three group 1 patients with pretreatment pubertal growth velocity of 2.7, 4.0 and 4.2 SD score decelerated their growth to 0, -0.6 and 2.9 SD score (this last patient had an unchanged breast stage), respectively, whereas the three group 2 patients, with growth velocities of 2.0, 4.0, and 4.3 SD score, decelerated their growth to -1.0, -2.6, and -2.9 SD score, respectively.
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BA/CA). In group 1 patients BA/CA decreased to levels less than 1, from 1.2 ± 0.7 to 0.75 ± 0.3. In group 2 patients BA/CA decreased to a greater extent, from 1.2 ± 0.7 to 0.6 ± 0.3 and 0.4 ± 0.2 in the first and second years of therapy, respectively (P < 0.05; Fig. 3).
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Discussion
The landmark report by Klein et al. (12) of higher prepubertal estrogen levels in girls than in boys opened a debate on the role of prepubertal estrogen. Multiple direct and indirect reports lend evidence to such a role in childhood growth (9, 10, 11). We now show that a prepubertal dose of estrogen replacement during gonadal suppression by GnRH therapy in CPP is effective for at least 24 months in maintaining normal growth velocity of about +1 SD score without acceleration of bone maturation beyond BA/CA of 1 or pubertal development.
The mini-dose of estrogen used here is based on an attempt to replace prepubertal estrogen levels (8, 12). It is much lower than the low dose estrogen employed for growth acceleration in girls with Turner syndrome. Based on the relative estrogenic activity of conjugated estrogen and ethinyl E2 (13) and a mean patient weight of 20 kg, it was calculated that the mini-dose is 12- to 28-fold weaker than the usual low dose of 100 ng/kg ethinyl E2 given for growth acceleration. The dose remains hypothetical, as we were unable to measure its pharmacokinetics with clinically available methodology. It remains to be studied whether prepubertal replacement dose of estrogen would influence prepubertal growth in patients with Turner syndrome.
The first working hypothesis was that estrogen levels are suppressed by GnRH agonist therapy below normal prepubertal levels. With the insufficiently sensitive assay used here, this has not been addressed in the current study, and we rely on a previous report that showed a dose-dependent suppression of serum E2 by a GnRH agonist (8).
The second hypothesis was that estrogen suppression is responsible for the slow growth of girls with CPP during GnRH agonist therapy. This seems to be supported by normalization of growth during estrogen replacement therapy as well as by previous direct and indirect evidence for the role of estrogen in childhood growth (9, 10, 11). Maintenance of a growth velocity SD score of about 1, with slightly faster bone maturation compared with controls, seems to indicate a mini-dose estrogen effect. These effects are best exemplified in three patients from each group who had fairly fast pubertal-type growth velocity. Whereas the control group decelerated their growth markedly, the estrogen-treated patients decelerated it only mildly. The sample size does not allow for separate statistics of these subgroups.
The third hypothesis was confirmed, and a mini-dose of estrogen replacement indeed normalized growth compared with that of patients receiving GnRH analog only, who slowed their growth markedly, with no significant acceleration of bone maturation. Estrogen accelerates bone maturation, as evident from delayed bone maturation in patients with mutated ER (14) or those with aromatase deficiency (15). Although in patients who had been receiving estrogen replacement bones matured faster than in the control group, the mini-dose was low enough to prevent bone maturation beyond a BA/CA of 1. Only long-term follow-up will reveal whether the difference is significant with respect to attainment of final height.
In most girls with CPP, GnRH agonist therapy nearly preserves genetic final height potential (1), and thus the deceleration observed during therapy has no consequence for final height. The present results are therefore mostly the proof of a concept, although it may be used clinically in a subgroup of CPP patients with short stature to prevent temporary deceleration of growth. At the same time, it raises questions about other possible consequences of prepubertal estrogen deficiency during GnRH agonist therapy. In the case of Turner syndrome, it was suggested that some of the cognitive deficiencies of the syndrome are due to estrogen deficiency, and that estrogen replacement in young Turner patients improves those deficiencies (16). Likewise, such replacement therapy might influence body composition, liver function, and biochemical markers of estrogen deficiency, as recently shown to be the case in Turner syndrome (17).
It is concluded on a pilot basis that a prepubertal mini-dose of estrogen replacement during GnRH therapy in patients with CPP is safe and effective for at least 24 months in maintaining normal prepubertal growth without acceleration of bone maturation or pubertal development. Until a similar full-scale study is performed in CPP patients, looking at variables other than growth, the current pilot results do not provide a justification for such therapy. It, rather, supports the emerging concept of a physiological role for prepubertal estrogen secreted by the ovaries.
Footnotes
Abbreviations: BA/CA, Rate of change in bone age per change in chronological age over 1 yr of observation was calculated; CPP, central precocious puberty.
Received February 22, 2001.
Accepted June 25, 2001.
References
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  L. Aksglaede, A. Juul, H. Leffers, N. E. Skakkebaek, and A.-M. Andersson The sensitivity of the child to sex steroids: possible impact of exogenous estrogens Hum. Reprod. Update, July 1, 2006; 12(4): 341 - 349. [Abstract] [Full Text] [PDF]
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) or GnRH analog therapy alone (group 2; 
). The horizontal line indicates the assays detection levels. Values are the mean ± SD. The analytical sensitivity of the assays (detection line) was 0.1 IU/liter for LH and FSH and 14 pmol/liter for E2.
